The process of vascular development is a highly stereotyped process that involves endothelial cell (EC) migration, proliferation, network assembly, and remodeling among other steps. To date, a significant number of molecules, mostly secreted factors produced by surrounding cells, have been shown to regulate vascular development. Vascular endothelial growth factor A (VEGFA) is critical to the development of the blood vasculature while VEGFC plays an equally important role in lymphatic vasculature development. The latter process involves a cell fate change resulting in the appearance of lymphatic endothelial cells (LECs) followed by proliferation, migration and sprouting of newly formed lymphatic vessels.
Although VEGFs importance is well established, contributions of other growth factors, and in particular that of the fibroblast growth factor (FGF) family, have not been defined. FGFs are known to play important role in stabilization and maintenance of the blood vasculature, but the role of these growth factors in vascular development remains unclear. Twenty-two members of the FGF family exert their biological effects via four distinct receptor tyrosine kinases (FGFR1-R4), each of which can exist in two different isoforms that determine its signal specificity. In addition, a number of auxiliary receptors, including syndecans and Klothos, regulate FGF signal transduction. This complexity of FGF biology presents distinct challenges to experimental studies of their biological roles.
Endothelial migration and sprouting, processes prominent in vascular development, are regulated by a number of different cytokines and growth factors that can activate contraction and proliferation machineries.
It is well established in the art that angiogenesis is implicated in the pathogenesis of a variety of disorders. In the case of tumor growth, angiogenesis appears to be crucial for the transition from hyperplasia to neoplasia, and for providing nourishment for the growth and metastasis of the tumor. The neovascularization allows the tumor cells to acquire a growth advantage and proliferative autonomy compared to the normal cells. This process involves a multitude of angiogenesis stimulators and inhibitors. In view of the role of angiogenesis in many diseases and disorders, various anti-angiogenic drugs and in particular anti-vascular endothelial growth factor (VEGF) agents have been developed such as Bevacizumab. However these drugs can be toxic and have many side effects such as, for example, bleeding.
There is an urgent need in the art for new methods of modulating vascular development, and particularly methods of inhibiting development or progression of angiogenesis. This invention addresses this need.